Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Abstract

A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications.

Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism

“…Chen et al . and Anderson demonstrated that MLT could suppress the translocation of glucocorticoid receptors and increase the expression of SIRT3, thereby modulating autophagy and mitophagy and inhibiting OP progression 105,106 . These findings provided a more comprehensive understanding of how MLT may serve as a therapeutic agent in counteracting OP.…”

“…Chen et al and Anderson demonstrated that MLT could suppress the translocation of glucocorticoid receptors and increase the expression of SIRT3, thereby modulating autophagy and mitophagy and inhibiting OP progression. 105,106 These findings provided a more comprehensive understanding of how MLT may serve as a therapeutic agent in counteracting OP. Muxel et al observed NF-kB-mediated enhancement of macrophage phagocytosis through MLT synthesis, which contributes to the functional specialization of macrophages that is essential for the innate immune defense.…”

Role of Melatonin in Viral, Bacterial and Parasitic Infections

“…Thus, the immunoenhancing action of MLT is linked to its circadian properties, including the receptor-mediated modulation of cytokine production, cell migration and antigen presentation to immunocompetent cells [ 44 , 45 ]. Last but not least, MLT may suppress the nuclear translocation of glucocorticoid receptors [ 46 ] and, hence, modulate their effect on immunity [ 47 ].…”

“…This effect involves the stimulation of cytokines such as IL-1β, IL-2, IL-6, IL-8, TNF-α, IFNγ and IL-17A and/or the upregulation of cyclooxygenase-2 (COX-2) and inducible NO synthase. Other effects are exerted on hematopoiesis by stimulating GM-CSF and the differentiation of Th cells and NK cells [ 46 ]. Yet, an excessive inflammatory response may have a paradoxical effect on immunity, leading to the activation of the coagulation system, organ failure and immunodeficiency by inducing T-cell apoptosis [ 49 ].…”

Role of the Night-Time Systemic Processes and the Astrocyte Tryptophan-Melatonin Pathway in the Regulation of α-Synuclein and Wider Parkinson’s Disease Pathophysiology

“…Generally, CAR, along with the corelease of adrenal aldosterone, is proposed to increase respiration and blood pressure in 'preparation for the coming day' [40]. However, recent work indicates that CAR may be an important regulator of pathophysiology across diverse medical conditions, including neurodegenerative conditions and cancer, as well as aging [41,42]. The GR is typically held in a cytoplasmic complex with heat shock protein (hsp)90 and p23.…”